Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HT influences a number of physiological functions and is implicated in a large number of central nervous system disorders and neurodegenerative diseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem. 2005, 40, 17].
One of the most actively studied 5-HT receptor subtypes is 5-HT1A, a 421 amino acid protein coded on human chromosome 5 by an intronless gene. 5-HT1A receptors are expressed in the central nervous system with highest density in the dorsal and median raphe nuclei as well as in the hippocampus. High density is also seen in the frontal cortex, entorhinal cortex, amygdale, and septum. 5-HT1A agonists and partial agonists have been implicated I and have demonstrated effectiveness in the treatment of anxiety and depression in the clinic. Partial agonists of the 5-HT1A receptor mediate antidepressant activity through an increase in serotonergic neurotransmission. Although the mechanism of action is not yet fully understood, there is substantial evidence that the physiological and behavioral responses are achieved following desensitization of the 5-HT1A receptor-mediated response.
According to the U.S. National Institute of Mental Health, generalized anxiety disorder and depression are the most prevalent mental illnesses. Most of the drugs used for treating anxiety and depression suffer from troublesome side effects. Selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin nonadrenaline reuptake inhibitors (SNRIs) exert their effects by increasing neurotransmitter availability and transmission. Another class of drugs used for the short-term relief of anxiety is benzodiazepines. These sedating agents are controlled substances because of their addictive properties and can be lethal when used in combination with alcohol.
The 5-HT1A agonists are safer and more effective therapeutic drugs for the treatment of anxiety and depression and potentially useful in the treatment of other CNS diseases including Alzheimer's, cognitive and memory dysfunction, frontotemporal dementia, sleep disorders, cognitive impairment associated with schizophrenia, pain, migraine, obesity and Huntington's disease,